Irritable Bowel Syndrome (IBS), and other persistent visceral pain syndromes such as interstitial cystitis/painful bladder syndrome present a heterogeneous group of patients with often overlapping symptoms. We hypothesize that biologically determined subsets of IBS patients are composed of distinct clusters of biological and behavioral endophenotypes. Some of the involved endophenotypes show sex-related differences, biasing most of these syndromes towards female predominance. Our SCOR research during the past funding period has enabled us to generate a group of testable candidate endophenotypes, many with sex differences, that relate to important clinical characteristics in functional GI disorders. We propose to test the general hypothesis that distinct subgroups of patients can be identified in a population meeting IBS symptom criteria using a phenomics approach in three Aims. In Aim A, we will prospectively perform comprehensive endophenotyping of 120 IBS patients (60 women). Multimodal brain imaging and psychophysiological techniqes, together with behavioral measures will be used to identify central endophenotypes related to stress hyperresponsiveness, pain sensitivity and cognitive modulation. These endophenotypes will be combined in a comprehensive data base with neuroendocrine (including HPA axis parameters studied in Project 1), and peripheral endophenotypes (including visceral adipose tissue [VAT] and adipokines, studied in Project 2). In Aim B, we will use interventional phenotyping using a corticotropin releasing factor type 1 receptor (CRF-R1) antagonist in 60 female IBS patients to test the hypothesis that a subgroup of IBS patients with an upregulated CRF/CRF-R1 signaling system can be identified by their responsiveness to a selective CRF-R1 antagonist, while other subgroups show minimal or no response. In Aim C we will apply advanced mathematical modeling techniques to identify patient subgroups from endophenotypes identified in Aims A and B to test the hypotheses that subgroups of IBS patients can be identified based on unique clusters of endophenotypes, that some of these endophenotypes are responsible for the greater female prevalence of IBS and related syndromes.